Medical device for delivering biologically active material

ABSTRACT

This invention relates generally to a stent comprising a plurality of struts and a plurality of projecting elements integral with the struts. At least some of the struts and some of the projecting elements comprise a biologically active material. The struts are configured in a tubular shape or tubular sidewall having two ends. One end of at least one of the projecting elements defines an end of the stent when the stent is expanded. The invention is also directed to a method for delivering the biologically active material to body tissue of a patient by inserting such an expandable stent into body of the patient. The invention is further directed to a system comprising the expandable stent and a balloon catheter for expanding the stent.

[0001] This is a continuation-in-part of U.S. patent application Ser.No. 10/062,794, filed Jan. 31, 2002, which is incorporated herein byreference.

FIELD OF THE INVENTION

[0002] This invention relates generally to medical devices, such asstents, for delivering a biologically active material to a desiredlocation within the body of a patient. More particularly, the inventionis directed to a medical device comprising a plurality of struts and aplurality of non-structural elements integral with the struts, whereinthe struts and the non-structural elements comprise the biologicallyactive material. The invention is also directed to a method fordelivering the biologically active material to the body tissue of apatient by inserting this medical device into the body of the patient,and further a method for designing such medical device.

[0003] The invention is also directed to a medical device comprising aplurality of struts and having an outer surface which has a middlesection and end sections. The end sections of the outer surface either(1) contain a greater amount of a biologically active material per unitlength of the outer surface or (2) have a greater capacity per unitlength to contain such material than the middle section of the outersurface by having a greater surface area per unit length of the outersurface than the middle section or having a greater affinity for thebiologically active material per unit length of the outer surface thanthe middle section.

[0004] Furthermore, this invention relates generally to a stentcomprising a plurality of struts and a plurality of projecting elementsintegral with the struts. At least some of the struts and some of theprojecting elements comprise a biologically active material. The strutsare configured in a tubular shape or tubular sidewall having two ends.One end of at least one of the projecting elements defines the end ofthe stent when the stent is expanded. The invention is also directed toa method for delivering the biologically active material to the bodytissue of a patient by inserting such an expandable stent into the bodyof the patient. The invention is further directed to a system comprisingthe expandable stent and a balloon catheter for expanding the stent.

BACKGROUND OF THE INVENTION

[0005] Balloon angioplasty has been very effective in treating stenosis,i.e., to open blocked vessels and restore normal levels of blood flow.However, although once a blocked vessel is opened, the treated vesselcan restenose, i.e., reclose, shortly after the procedure. Thus,patients may have to undergo repeated angioplasty or even surgery.

[0006] Implantable stent prosthesis or stents are used to reducerestenosis after balloon angioplasty or other procedures usingcatheters. A stent in the form of a wire mesh tube props open an arterythat has recently been cleared using angioplasty. A balloon expendablestent is collapsed to a small diameter, placed over an angioplastyballoon catheter and moved into the area of the blockage. When theballoon is inflated, the stent expands, locks in place and forms ascaffold to hold the artery open. A self-expandable stent is collapsedto a small diameter by placing in a sheath, and expands in the area ofthe blockage when the sheath surrounding the stent is removed. Usually,the stent stays in the artery permanently, holds it open, improves bloodflow to the heart muscle and relieves symptoms. The stent procedure isfairly common, and various types of stents have been developed andactually used.

[0007] A variety of medical conditions have been treated by introducingan insertable medical device having a coating for release of abiologically active material. For example, various types of biologicallyactive material-coated medical devices, such as stents, have beenproposed for localized delivery of the biologically active material to abody lumen, such as to reduce the possibility of restenosis. See, e.g.,U.S. Pat. No. 6,099,562 to Ding et al. However, it has been noted that,with existing coated medical devices, the release profile of abiologically active material may not be uniform along the entire lengthof the medical device.

[0008] For example, even if a biologically active material having apharmacological effect is delivered to a body tissue, such effect maynot result if the concentration of the biologically active material inthe body tissue is below a certain concentration. Such concentration isreferred to as the minimum effective concentration (C_(min)) of thebiologically active material in the body tissue. Each biologicallyactive material has different C_(min). C_(min) of a biologically activematerial also varies depending on the type of body tissue to which it isdelivered. On the other hand, a biologically active material becomestoxic if its concentration is higher than a certain concentration. Suchconcentration is referred to as the maximum effective concentrationC_(max). In addition, it is insufficient that the mean concentration ofthe biologically active material delivered through out the body tissueto be treated is greater than C_(min) and smaller than C_(max). Theconcentration of the biologically active material at each and every areathroughout the body tissue to be treated should be equal to or greaterthan C_(min) but equal to or smaller than C_(max)of the biologicallyactive material. For instance, when a coated stent comprised of struts,such as the stent shown in FIG. 1, is used as a medical device fordelivering a hydrophobic biologically active material, concentrations ofthe biologically active material may significantly differ between theregions of the tissue adjacent to the struts and the regions of thetissue farther from the struts. See Hwang et al.,http://www.circulationaha.org (accepted in April 2001). Even if the meanconcentration of the biologically active material in the tissuesurrounding the stent is above C_(min) of the biologically activematerial and at or under C_(max), the concentrations at certain regionsof the tissue to be treated, which are farther from the struts, may notreach C_(min). Also, if the amount of the biologically active materialin the coating is increased to achieve a concentration higher thanC_(min) at all regions of the tissue to be treated, then theconcentrations at regions of the tissue adjacent to the struts mayexceed the toxic levels, as explained below using the figures.

[0009] In FIG. 1, the coated stent 10 is placed in a blood vessel 15having a vessel wall 12 to be treated. This vessel wall is surrounded bytissue 12 a. The biologically active material coated on struts 13 of thestent 10 is released into the vessel wall 12 to be treated. FIG. 2 is across sectional view along line A of the stent 10 in FIG. 1. FIG. 2 alsoshows the concentration levels of the biologically active material ineach area surrounding the struts 13 at a certain time after theinsertion of the stent into the vessel 15. The area adjacent to thestruts, i.e., the area between the struts 13 and line 16, has aconcentration level at or below C_(max), which is just below the toxiclevel. The farther from the struts 13 the tissue to be treated islocated, the lower the concentration of the biologically active materialdelivered to the tissue becomes. However, the area between line 18 andline 19 has the concentration level at or higher than C_(min). Aconcentration of the biologically active material in the area outsideline 19 is below C_(min).

[0010] Also, FIGS. 2A and 2B clearly show that there are gaps betweeneach strut 13 wherein the vessel wall to be treated does not receivesufficient biologically active material to have C_(min). The areaswithin line 19, i.e., having concentrations above C_(min), may beincreased in size to include more area of the vessel wall 12 to betreated, if the amount of the biologically active material on the struts13 is increased. However, by doing so, the concentration of thebiologically active material in the area adjacent to the struts 13 mayexceed the toxic level. Accordingly, there is a need for a medicaldevice comprising a plurality of struts that can achieve thebiologically active material concentration that is above C_(min) andbelow toxic levels throughout the tissue.

[0011] Also, generally with existing coated medical devices, the coatingis uniformly applied along the entire length of the device or surface ofthe device. For example, conventional coated stents are coated uniformlyalong the entire length of the surface of the device. The biologicallyactive material-concentration-profile along the length of the coatedsurface may be in the shape of a bell-curve, wherein the concentrationof the biologically active material released at the middle of thesurface is greater than the concentration of the biologically activematerial released at the ends of the coated surface. This unevenconcentration-profile along the length of the coated surface may lead tothe application of an inadequate or sub-optimal dosage of thebiologically active material to the body tissue located at the ends ofthe coated surface. It is possible that such uneven local concentrationof the biologically active material along the length of the coatedsurface of the medical device may lead to undesired effects. Forexample, in the case of a biologically active material-coated stent usedto prevent or treat restenosis, if the amount of biologically activematerial delivered to the tissue located at the ends of the stent issub-optimal, it is possible that restenosis may occur in such tissue. Infact, recent data show that restenosis occurs at the edges of the stentsabout five times more often than at the middle portion of stents, i.e.,the “edge effect”. The “edge effect” may be caused by the lesserconcentration of biological active material that is present in bodytissue in proximity to the edges of the stent.

[0012] The biologically active material dosage at the tissue located atthe ends of the coated surface of the medical device can be increased ifthe concentration or amount of the biologically active material isincreased along the entire length of the surface. However, by increasingthe concentration or amount of biologically active material releasedalong the entire surface, the dosage delivered to tissue located at themiddle of the surface may be too great or even at toxic levels. Thus,there is a need for a medical device that can realize a more uniformconcentration-profile for biologically active material along the entirelength of a coated surface of a medical device and avoid the possibilityof undesired effects accompanied by an uneven biologically activematerial concentration-profile.

[0013] Moreover, medical devices wherein a biologically active materialis uniformly coated on the entire outer surface of the medical devicesthat is exposed to body tissue are generally used to deliver suchbiologically active material to specific parts of such body tissue. Forinstance, such devices are used to treat lesions in body lumen. However,because the entire outer surface of the device contains the biologicallyactive material, this biologically active material will be delivered tohealthy body tissue in addition to the lesion. Treatment of healthytissue with the biologically active material is not only unnecessary butmaybe harmful. Accordingly, there is a need for a medical device thatcan realize an asymmetry release-profile of biologically active materialto deliver such material to only a limited region of the body tissuethat requires the biologically active material.

[0014] Also, the pressure or stress that the stent exerts against thesurrounding tissue is concentrated at the edges of the stent. Suchconcentrated stress may also contribute to the “edge effect”. Therefore,to reduce the “edge effect,” there is a need for a stent having astructure wherein the stress exerted against the body tissue inproximity to the edges of the stent is reduced and such body tissue isexposed to a greater amount of biologically active material.

[0015] Furthermore, when a balloon and a balloon expandable stentdisposed on the balloon are expanded, the ends of the stent generally donot extend to the ends of the balloon, i.e., the ends of the stent donot cover the entire balloon's length. Thus, the balloon inflates beyondthe margins or ends of the stents, and the portions of the balloonbeyond the stents' ends directly contact the patient's lumen wall. Suchdirect contact with the balloon may cause a tissue injury in thepatient's lumen wall. Also, to reduce such potential injury by using aballoon having a length which is matched exactly to a stent length isimpractical because: (1) it is difficult to align the stent with theballoon during crimping; (2) both stent and balloon are manufacturedwithin a small but finite tolerance that provides a range of componentsizes; and (3) stents will be shortened during expansion. Therefore,there is a need for a stent having structure to reduce such potentialinjury caused by the ends or edges of the balloon.

SUMMARY OF THE INVENTION

[0016] These and other objectives are accomplished by the presentinvention. To achieve the aforementioned objectives, we have invented amedical device for delivering a biologically active material into a bodytissue of a patient; a method for designing such device; and a methodfor delivery of a biologically active material to a body tissue.

[0017] The medical device of the invention is a medical device fordelivery of biologically active materials to a body tissue of a patientin need of treatment. The medical device comprises struts andnon-structural elements integral with the struts, and those struts andnon-structural elements comprise the biologically active material. In anembodiment, the medical device comprises a tubular portion having anouter surface, and the non-structural elements are distributedthroughout the outer surface. In another embodiment, the non-structuralelements are located in a radially asymmetric distribution on the outersurface. In yet another embodiment, the outer surface has end sectionsand a middle section, and the end sections comprise a greater number ofthe non-structural elements per unit length of the outer surface thanthe middle section.

[0018] The present invention is also directed to a method for deliveringa biologically active material to the body tissue of a patient whichcomprises inserting the above-mentioned medical device into the body ofthe patient.

[0019] Further, the present invention is directed to a method fordesigning such medical device. The method comprises: providing apreliminary medical device comprising struts in a geometric patternwherein the struts comprise the biologically active material;determining a concentration-profile for the biologically active materialwhich is released from the preliminary medical device; and modifying thegeometric pattern of the struts of the preliminary medical device byincorporating non-structural elements comprising the biologically activematerial that are integral with the struts to achieve more desireddistribution of the biologically active material in the body tissue.

[0020] The present invention is also directed to a medical deviceinsertable into the body of a patient. The medical device has an outersurface comprising struts, and the outer surface has a middle sectionand end sections. The end sections have a greater available surface areaper unit length of the outer surface than the middle section. In anotherembodiment, the end sections have greater affinity for the biologicallyactive material per unit length of the outer surface than the middlesection. In yet another embodiment, the end sections have a greateramount of the biologically active material per unit length of the outersurface than the middle section. Further, in another embodiment, atleast a part of each of the middle section and the end sections iscovered with a coating comprising the biologically active material, andthe middle section comprises a barrier layer placed over the coatingcovering the middle section.

[0021] Moreover, the present invention provides another embodiment ofthe medical device for treating body tissue. The medical devicecomprises an outer surface comprising struts. The outer surface has arectangular portion having a greater capacity for carrying or containinga biologically active material per unit length of the outer surface thanthe parts of the outer surface that are outside the rectangular portion.In the alternative, the rectangular portion may have a greater affinityfor the biologically active material. The present invention is alsodirected to a method for delivering a biologically active material byinserting the above-mentioned medical device comprising the biologicallyactive material in such a way that the rectangular portion is in directcontact with the body tissue in need of treatment.

[0022] Additionally, the present invention is directed to an expandablestent comprising two ends and a tubular sidewall between the two ends.The sidewall comprises a plurality of struts, and a plurality ofprojecting elements located proximate at least one stent end. Eachprojecting element comprises a first end and a second end, in which thefirst projecting element end is integral with or attached to a strut.The second projecting element end is capable of defining at least onestent end when the stent is in an expanded position. Also, at least oneof the struts or at least one of the projecting elements comprises abiologically active material.

[0023] Moreover, the invention is directed to a balloon expandable stentcomprising two ends and a tubular sidewall between the two ends, inwhich the sidewall comprises a plurality of struts and a plurality ofprojecting elements proximate at least one stent end. Each projectingelement comprises a first end and a second end. The first projectingelement end is integral with or attached to a strut; and the secondprojecting element end is capable of defining at least one stent endwhen the stent is in an expanded position. At least one of theprojecting elements comprise a biologically active material.

[0024] In addition, the present invention is directed to a systemcomprising a balloon expandable stent and a balloon catheter having aninflatable balloon for expanding the stent to an expanded position. Thestent comprises two ends and a tubular sidewall between the two ends,and the sidewall comprises a plurality of struts as well as a pluralityof projecting elements proximate at least one stent end. Each projectingelement comprises a first end and a second end. The first projectingelement end is integral with or attached to a strut; and the secondprojecting element end is capable of defining at least one stent endwhen the stent is in the expanded position. Also, at least one of thestruts or one of the projecting elements comprise a biologically activematerial.

BRIEF DESCRIPTION OF THE DRAWINGS

[0025]FIG. 1 depicts a side view of a stent without non-structuralelements in a cross-sectioned blood vessel. The stent is coated with abiologically active material.

[0026]FIGS. 2A and 2B depict cross sectional views of the stent andblood vessel of FIG. 1 along line A-A and line B-B (shown in FIG. 2A),respectively. FIGS. 2A and 2B also show areas of body tissue havingdifferent concentration levels of the biologically active material.

[0027]FIG. 3 depicts a side view of a stent with non-structural elementsin a cross-sectioned blood vessel. The stent is coated with abiologically active material.

[0028]FIGS. 4A and 4B depict cross sectional views of the stent andblood vessel of FIG. 3 along line C-C and line D-D (shown in FIG. 4A),respectively. FIGS. 4A and 4B also show areas having differentconcentration levels of the biologically active material.

[0029]FIG. 5 depicts struts of a conventional expandable stent.

[0030]FIGS. 6-14, each depicts struts having non-functional elementsintegral with the struts.

[0031]FIG. 15 depicts wavy struts that have greater surface area perunit length of the strut than conventional struts.

[0032]FIG. 16 depicts struts having a greater average diameter perlength of the strut than the conventional struts.

[0033]FIG. 17 depicts a simplified view of a stent having a rectangularportion of the outer surface where non-structural elements are located,and the rectangular portion is shown by hatching.

[0034]FIG. 18 depicts a perspective view of a stent whereinnon-structural elements are located only in a rectangular portion of theouter surface.

[0035]FIG. 19 depicts a stent having end sections and a middle sectionand comprised of struts, wherein the end sections are comprised of aporous material and the middle section is comprised of a less porousmaterial.

[0036]FIG. 20 is a simplified view of a stent which shows the outersurface, having end sections and a middle section.

[0037]FIG. 21 depicts a side view of a stent comprised of a plurality ofstruts and projecting elements in an unexpanded state.

[0038]FIG. 22 depicts the stent of FIG. 21 in an expanded state.

[0039]FIG. 23 depicts a projecting element in a shape of a rod having arectangular-end integral to a strut.

[0040]FIG. 24 depicts another projecting element in a shape of a rodhaving a paddle-shaped end integral to a strut.

[0041]FIGS. 25a-27 a depict projecting elements in the shape of rodshaving various shaped ends integral to a strut.

[0042]FIG. 28 depicts a part of an unexpanded stent where the projectingelements are in the shape of a rod with an opening such as a loop at itsend.

[0043]FIG. 29 shows the stent of FIG. 28 in an expanded state.

DETAILED DESCRIPTION OF THE INVENTION 1. Medical Device for DevelopingBiologically Active Material with Desired Distribution

[0044] 1.1 Non-Structural Elements

[0045] Even if a biologically active material having a pharmacologicaleffect is delivered to a body tissue, such effect may not result if theconcentration of the biologically active material in the body tissue isbelow a certain concentration (C_(min)). On the other hand, abiologically active material becomes toxic if its concentration ishigher than a certain concentration (C_(max)). The concentration of thebiologically active material at each and every area throughout the bodytissue to be treated should be at or above C_(min) but at or underC_(max) of the biologically active material.

[0046] When the medical device is comprised of a plurality of strutscomprising a biologically active material, the body tissue located at ornear a center of each “cell” of the medical device, i.e., openingsbetween the struts, tends to have the lowest concentration of thebiologically active material. Such concentration can be below C_(min).This is particularly true when the biologically active material ishydrophobic. When the concentration of the biologically active materialin the tissue located at the center of each cell is lower than C_(min),the concentration can be increased by increasing the amount of thebiologically active material coated on outer surface of each strut.However, then the concentration at the tissue adjacent to the struts mayexceed C_(max).

[0047] For example, FIG. 1 depicts a coated stent 10 having aconventional geometric pattern, which is placed in a blood vessel 15having a vessel wall 12 to be treated. The biologically active materialcoated on struts 13 of the stent 10 is released into the vessel wall 12to be treated. FIGS. 2A and 2B show cross sectional views along line A-Aand line B-B (shown in FIG. 2A) of the stent 10 in FIG. 1 and theconcentration levels of the biologically active material in each areasurrounding the struts 13 at a certain time after the stent 10 wasinserted into the blood vessel 15. The area adjacent to the struts,i.e., the area between the struts 13 and line 16 has a concentrationlevel at or below C_(max), which is just below the toxic level. Thefarther from the struts 13 the area is located, the lower theconcentration becomes. Thus, the concentration levels gradually decreasefrom the area between lines 16 and 17, the area between 17 and 18, tobetween 18 and 19. The area between line 18 and line 19 has aconcentration level at or higher than C_(min). A concentration of thebiologically active material in the area outside line 19 is belowC_(min), and thus the pharmacological effects of the biologically activematerial does not result in the area.

[0048] Furthermore, FIGS. 2A and 2B clearly show that there are gapsbetween each strut 13, i.e., near the center of cells, wherein thevessel wall to be treated does not receive sufficient biologicallyactive material to have C_(min). The size of the area within line 19,i.e., the areas having the concentrations above C_(min), may beincreased to include the entire area of the vessel wall 12 to be treatedif the amount of the biologically active material on the struts 13 isincreased. However, by doing so, the area adjacent to the struts 13 maybe also increased and exceed the toxic level. Therefore, there is a needfor a medical device that can ensure the concentration of thebiologically active material throughout the body tissue to be treated isat least C_(min) and at most C_(max).

[0049] To achieve such a desired distribution of a biologically activematerial throughout the body tissue to be treated, the embodiments ofthe medical device of the present invention comprise a plurality ofstruts and a plurality of non-structural elements integral to thestruts. The struts and non-structural elements comprise the biologicallyactive material. These non-structural elements are used to adjust thedistribution of the biologically active material in the body tissue sothat the desired concentration-profile for the biologically activematerial released from the medical device into the body tissue can beachieved. For instance, the medical device of the present invention canachieve concentrations higher than C_(min) at the tissue located at thecenter of cells without increasing the local concentration at an areaadjacent to the struts higher than C_(max).

[0050] An example is shown in FIGS. 3, 4A and 4B. FIG. 3 depicts acoated stent 10 which is obtained by modifying the conventionalgeometric pattern of stent 10 shown in FIG. 1 by incorporatingnon-structural elements 14 integral to the struts 13. The stent 10 isplaced in a blood vessel 15 having a vessel wall 12 to be treated. Thebiologically active material coated on struts 13 and non-structuralelements 14 of the stent 10 is released into the vessel wall 12 to betreated and tissue 12a surrounding the vessel wall 12. FIGS. 4A and 4Bshow cross sectional views along line C-C and D-D (shown in FIG. 4A) ofthe stent 10 in FIG. 3 and the concentration levels of the biologicallyactive material in each area surrounding the struts 13 and thenonstructural elements 14 at a certain time after the stent 10 wasinserted in the blood vessel 15. The area adjacent to the struts, i.e.,the area between the struts 13 or the nonstructural elements 14 and line16 has a concentration level from at or below C_(max), which is justbelow the toxic level. The farther from the struts 13 or thenonstructural elements 14 the area is located, the lower theconcentration becomes. The area between line 18 and line 19 has theconcentration level at or higher than C_(min). FIG. 4A clearly showsthat the stent 10 can achieve concentrations higher than C_(min)throughout the entire area of the vessel wall 12 to be treated, even atareas located at the center of cells, without increasing theconcentration at areas adjacent to the struts above C_(max).

[0051] The term “non-structural element” refers to an element integralwith a strut, which can project from the strut or can be located alongthe strut. Such non-structural elements have substantially no effect onthe mechanical properties of the struts, such as, for example, (1)radial strength, (2) longitudinal flexibility, (3) expansion ratio, (4)trackability and (5) profile of a medical device comprising theplurality of struts. In embodiments of the medical device of the presentinvention, the non-structural elements are integral with the struts,namely, they are generally made from the same material as the struts andare formed as a continuous part of the struts. Preferably, thenon-structural elements and struts may be manufactured simultaneously;for example, struts having non-structural elements can be laser-ablatedfrom a plate of metal or polymer.

[0052]FIG. 5 depicts example of conventional struts withoutnon-structural element, and FIGS. 6-14 depict examples of non-structuralelements integral with the conventional struts. Shapes of thenon-structural elements include, but not limited to, a straight rod (21in FIG. 6), a cone (22 in FIG. 7), a truncated cone (not shown), a hoop(23 in FIG. 8), a knot (24 in FIG. 9), a bent rod (25 in FIG. 10), anoval (26 in FIG. 11), and a rod having heads at its ends (27 in FIG. 12and 28 in FIG. 13). Bends in the struts (29 a and 29 b in FIG. 14) canbe used as non-structural elements so long as they do not affect themechanical properties of the struts.

[0053] This embodiment of the medical device of the present inventioncan be used for delivering any kind of biologically active material.Preferably, the biologically active material is hydrophobic, e.g.,paclitaxel, actinomycin, sirolimus, tacrolimus, everolimus,dexamethasone, halofuginone and hydrophobic nitric oxide adducts. Otherexamples of the biologically active material, coatings containing thebiologically active material, and examples of the medical device areexplained later in this application.

[0054] 1.2 Designing Medical Devices Having Struts and Non-StructuralElements

[0055] The present invention is directed to a method for designing amedical device comprising a plurality of struts and non-structuralelements integral with the struts for delivering a biologically activematerial to a body tissue of a patient. As explained above, when thestruts are placed in a certain geometric pattern, the concentration of abiologically active material at a center of each cell may not reachC_(min) of the biologically active material. However, the method of thepresent invention provides a geometric pattern of the struts in whichthe concentration of a biologically active material above C_(min) can beachieved throughout the body tissue to be treated without increasing theconcentration at the tissue located adjacent to the struts aboveC_(max).

[0056] In the method of the invention, a preliminary medical devicecomprising a plurality of struts in a geometric pattern is modified byincorporating non-structural elements to the struts to improve theconcentration-profile for the biologically active material released fromthe device to the body tissue to be treated. Any medical devicecomprising a plurality of struts in a geometric pattern, such as stent,can be used as a preliminary medical device for the method of theinvention provided that the struts comprise a biologically activematerial.

[0057] In the method of the present invention, a concentration-profilefor the biologically active material delivered to the body tissue fromthe preliminary medical device is determined. From this profile, theareas of tissue in which the concentration of the biologically activematerial is below Cmin can be determined. Such areas are then correlatedto the parts of the geometric pattern of the struts of the preliminarymedical device that were in contact with or near such areas.

[0058] The determination of such concentration-profile can be conductedby actually measuring concentrations using the biologically activematerial in vitro with a tissue model, which is similar to the bodytissue to be treated, such as cannulated animal arteries withsurrounding tissue or an artificial tissue, or in vivo with an animalmodel, such as rabbits or pigs. The biologically active material usedfor the experiment may be labeled with a fluorescence, a radioactivematerial or dye. Such labeled biologically active material is coated onthe medical device, and then the coated medical device is inserted intothe tissue model, or artificial tissue, or implanted in an animal.Alternatively, the biologically active material may be detected usingstandard GLP separation, mass spectroscopy or other direct analyticalmethods. After insertion, the tissue may be appropriately sectioned, andthe concentration-profile for the labeled biologically active materialis measured by a means appropriate to the label employed for theexperiment. However, a necessary care should be taken that the labelwould not greatly affect the diffusion of the biologically activematerial itself.

[0059] However, the concentration-profile may also be determined bymathematical simulation. For example, assuming a simple diffusion model,such simulation can be conducted by using the following conditions andequations:$\frac{\partial C}{\partial t} = {{D_{x}\left( \frac{\partial^{2}C}{\partial x^{2}} \right)} + {D_{z}\left( \frac{\partial^{2}C}{\partial z^{2}} \right)}}$

[0060] wherein C refers to a concentration of the biologically activematerial in the body tissue, x refers to a distance from the medicaldevice along x axis which is perpendicular to a boundary between themedical device and the body tissue, z refers to a distance from themedical device along z axis which is parallel to the boundary, Dx refersto a diffusion coefficient of the biologically active material indirection along x axis, Dz refers to a diffusion coefficient of thebiologically active material in a direction along z axis. For example,such x axis and z axis are shown in FIGS. 1, 2B, 3 and 4B. Dx and Dz canbe determined by the experiments using the labeled biologically activematerial in vitro or in vivo as described above. C=0 at t=0, whereinboundary conditions are as follows:

at a common boundary between the struts and the body tissue (atx=0):  (i)

[0061]${D_{x}\frac{\partial C}{\partial x}} = {h_{1}\left( {C - C_{\Gamma}} \right)}$

[0062] wherein C₁ refers to a concentration of the biologically activematerial in the struts, and h₁ refers to a mass transfer coefficient.Value of h₁ can be determined by the same experiments described above ordetermined by assumption based on the information known to one skilledin the art;

at a boundary between blood flow and the body tissue (at x=0):  (ii)

[0063]${D_{x}\frac{\partial C}{\partial x}} = {h_{2}\left( {C - 0} \right)}$

[0064] wherein h₂ refers to another mass transfer coefficient. Value ofh₂ can be determined by the same experiment mentioned above ordetermined by assumption based on the information known to one skilledin the art;

at an adventitial side of vascular wall (at x=L):  (iii)

[0065]${D_{x}\frac{\partial C}{\partial x}} = {- {h_{3}\left( {C - 0} \right)}}$

[0066] wherein h₃ is yet another mass transfer coefficient, and L is awidth of a region of interest. Value of h₃ can be determined by the sameexperiment mentioned above or determined by assumption based on theinformation known to one skilled in the art; and

“symmetry” (no-flux) boundary conditions at certain cross-sectionsperpendicular to z axis:  (iv)

[0067]${\frac{\partial C}{\partial z}\left( {z = 0} \right)} = {{\frac{\partial C}{\partial z}\left( {z = L_{z}} \right)} = 0}$

[0068] wherein Lz is the length along z axis of a region of interest.

[0069] Although a simplified model based on two diffusion coefficientsof the biologically active material in two directions, i.e., depth ofthe tissue penetration and the distance diffused, is described above asan example, there are more complex models which can be also employed forthe method of the present invention. Such complex models may furtheraccount for other variables, such as convection, vessel wallinhomogeneties, the type of cells, the lesions, the variabilitiesbrought by different coatings or coating porosity, blood flow, bodytemperature, blood pressure, and/or pressure of the implant against thevessel wall.

[0070] Subsequent to determining the concentration-profile for thebiologically active material which is released from the preliminarymedical device, the geometric pattern of the preliminary medical deviceis modified by incorporating a plurality of non-functional elements thatare integral with the struts to achieve more desired distribution of thebiologically active material in the body tissue to be treated. Thenon-structural elements also comprise the biologically active material.For example, the area of tissue in which the concentration of thebiologically active material is below C_(min) is determined from theconcentration-profile. Then, it is determined which parts of thegeometric pattern of the struts of the preliminary medical device werein contact with or near such areas. The non-structural elements can beincorporated near such parts in the geometric pattern, so that thebiologically active material released from the non-structural elementswould change the concentration in those areas.

[0071] For example, a stent 10 having a plurality of struts 13 in aconventional geometric pattern in FIG. 1 can be provided as thepreliminary medical device. The struts 13 are coated with a biologicallyactive material. Then, a concentration-profile in a body tissue for thebiologically active material which is released from the struts 13 isdetermined. An example of such profile is shown in FIGS. 2A and 2B withthe cross-sectional views of the stent 10 in the blood vessel 15. Thedetermination of such concentration-profile can be conducted by actuallymeasuring concentrations or by mathematical simulation as mentionedabove. According to the obtained concentration-profile, the geometricpattern of the struts 13 of the preliminary stent 10 are modified withnon-structural elements 14, for example, as shown in FIG. 3. FIGS. 4Aand 4B show the concentration-profile views for the biologically activematerial in the vessel wall 12. When the concentration-profile in thevessel wall 12 to be treated shown in FIGS. 2A-B and 4A-B are compared,in FIGS. 4A-B, the concentrations generally throughout the entire areaof the vessel wall 12 to be treated are above C_(min) and below C_(max).It is clear that the modified stent 10 achieves a more desirableconcentration-profile in the vessel wall 12 to be treated with thebiologically active material than the preliminary stent 10.

[0072] Preferably, after a concentration-profile for the biologicallyactive material in the body tissue which is released from the modifiedpreliminary medical device is determined, if there is an area of thebody tissue having the local concentration of the biologically activematerial lower than C_(min), then the device is modified again by addingnon-structural elements to the struts. In addition to or instead ofmerely adding additional non-structural elements, the non-structuralelements which have been already added can be removed or relocatedaccording to the determined concentration-profile. Consequently, amedical device having further improved delivery of the biologicallyactive material is obtained. If necessary, the determination step andthe modification step explained above can be repeated as many aspossible.

[0073] 1.3 Medical Device with Radially Asymmetric Area HavingNon-Structural Elements

[0074] The prior sections (section 1.1 and 1.2) explained hownon-structural elements can be added to a preliminary medical device toachieve a more desired concentration-profile for the biologically activematerial released from the device into body tissue. When the entireouter surface of a medical device, which comprises the plurality ofstruts and non-structural elements, is used to treat body, thenon-structural elements should be positioned uniformly throughout theentire outer surface of the medical device.

[0075] However, if the body tissue to be treated is smaller in surfacearea than the entire outer surface of the medical device, then thenon-structural elements do not have to be positioned throughout theentire surface of the medical device. For example, the medical devicecan comprise a tubular portion comprising an outer surface, such as astent, which comprises a plurality of struts and a plurality ofnon-structural elements. The non-structural elements located in aradially asymmetric distribution, such as shown in FIG. 17 where 33represents the location of the non-structural element on outer surfaceof a simplified figure of a stent 32. In this figure, the non-structuralelements are distributed only in a rectangular portion of the outersurface. FIG. 18 depicts a perspective view of a stent 34 whereinnon-structural elements 36 are provided onto the struts 35 only in arectangular portion of the outer surface. Such rectangular portion maybe parallel to longitudinal axis of the tubular portion and may have thesame length as that of the tubular portion. The rectangular portion ispreferably from about 25% to about 75% of the entire outer surface.

[0076] The present invention is also directed to a method for deliveringa biologically active material to body tissue using the above-mentionedmedical device, which comprises a tubular portion comprising an outersurface which comprises a plurality of struts and a plurality ofnon-structural elements, and the non-structural elements are located ina radially asymmetric distribution on the outer surface. In the method,the medical device is inserted into the body of the patient. Preferably,the non-structural elements are distributed only in a rectangularportion of the outer surface, and the medical device is inserted in sucha way that the rectangular portion is in direct contact with the bodytissue to be treated. In this way, the body tissue to be treated willreceive desired distribution of the biologically active material. On theother hand, the body tissue which does not need to be treated will beexposed to a lesser amount of the biologically active material.

2. Increased Capacity of the End Sections for Carrying or Containing aBiologically Active Material

[0077] In other embodiments of the medical device insertable into thebody of a patient of the invention, the medical device comprises anouter surface comprising a plurality of struts, and the end sections ofthe outer surface have a greater capacity per unit length of the outersurface for carrying or containing a biologically active material thanthe middle section of the outer surface. Specifically, in one embodimentof the medical device, each strut at the end sections has greateravailable surface area per unit length of the outer surface than themiddle section. In another embodiment, the end sections have a greateraffinity for the biologically active material per unit length of theouter surface than the middle section.

[0078] The medical device of the present invention may be manufacturedwith or without a biologically active material by a manufacturer. Whenthe medical device of the present invention is manufactured without abiologically active material, a practitioner (e.g., a medical doctor ora nurse) can apply the biologically active material to the medicaldevice. In either case, since the end sections of the outer surface havea greater capacity per unit length of the outer surface for carrying orcontaining the biologically active material than the middle section, theend sections will carry a greater amount of the biologically activematerial when the biologically active material is applied to the medicaldevice without needing to change application method of the biologicallyactive material to the end sections and the method to the middlesection. Therefore, when a practitioner applies to the outer surface ofthe medical device, such as by dipping, a coating composition containinga biologically active material, a larger amount of the biologicallyactive material per unit length of the outer surface will be depositedat the end sections than the middle section.

[0079] The term “unit length of the outer surface” refers to the lengthon an imaginary straight line along the outer surface drawn between apoint on an edge of the outer surface and another point on the opposingedge of the outer surface. Therefore, the terms, such as “capacity perunit length of the outer surface,” “available surface area per unitlength of the outer surface,” and “amount per unit length of the outersurface,” refer respectively to the capacity, available surface area andamount per unit length of the imaginary straight line explained above.

[0080] 2.1 Increased Available Surface Area at the End Sections

[0081] As explained above, one of the embodiments of the medical devicehas end sections which have greater available surface area per unitlength of the outer surface than that of the middle section. The term“available surface area” refers to a surface area which is available tobe coated by a coating composition comprising a biologically activematerial.

[0082] One way of increasing the available surface area of the endsections is to fabricate the outer surface of the medical device usingmore material at its ends. For example, when the medical device iscomprised of struts, the available surface area per unit length of theouter surface in the end sections is increased by adding non-structuralelements to the struts. The non-structural elements are explained above(see section 1.1). The end sections comprise a greater number of thenon-structural elements per unit length of the outer surface than themiddle section. The middle section may have smaller number of thenon-structural elements or no non-structural elements.

[0083] Further, the available surface area can be increased byincreasing the surface area of the struts themselves. For example, wavystruts 30 shown in FIG. 15 can have more outer surface area per lengththan straight struts shown in FIG. 5. Also, struts having greateraverage diameter, such as struts which are thicker or wider at certainportion 31 shown in FIG. 16, have greater outer surface area per lengththan struts which have smaller average diameter. Moreover, the endsections of the outer surface can be made to have greater availablesurface area by roughing the struts' outer surface or providingindentations or grooves on the struts' surface. The above-mentioned wavystruts, wider or thicker struts, indentations and grooves may havevarious shapes, so long as such structure does not affect stentsstructural functions. For example, the above-mentioned structure shouldnot hinder self-expansion of a self-expanding stent and should not causeany harm to the patient body. The above-mentioned wavy struts,indentations and grooves can be manufactured by laser ablation.

[0084] In another embodiment in which the capacity of the end sectionsto carry or contain the biologically active material is greater than thecapacity of the middle section, the end sections of the outer surfaceare more porous, and the middle section of the surface is relativelyless porous. The middle section may also be non-porous. For example, inFIG. 19, the circles 45 and 47 show enlarged portions of the outersurface of the struts 42 of a stent 40 in the middle section 44 and endsection 46, respectively. The surface of the struts in the end section46 has more pores 48 than the surface of the struts at the middlesection 44. In such embodiment, the end sections 46 have a greateravailable surface area per unit length of the outer surface than that ofthe middle section 44 since the pores 48 increase available surfacearea.

[0085] The end sections of the outer surface may be made porous byforming the end sections of the outer surface themselves from a porousmaterial or by forming the end sections with a non-porous material andthen covering the end sections with a porous coating layer. For example,porous metal struts can be prepared by sintering metal, i.e., molding orpressing metal particles into a desired shape and heating them to atemperature slightly below the melting point of the metal. Porosity canbe changed by using different particle sizes and/or dimensions and/ordifferent temperatures. Also, porous metal struts can be prepared byusing metal filaments or fibers. See e.g. U.S. Pat. No. 5,843,172 issuedto Yan which discloses examples of struts made of porous materials,which is incorporated herewith by reference.

[0086] The end sections of the outer surface may be made porous bycoating with a porous coating layer. A porous coating layer may beprepared, for example, by applying a mixture of a polymer, an elutableparticulate material and a solvent on a surface to form a layer, andthen eluting the elutable particulate material from the layer. Thefollowing is a detailed description of suitable materials and methodsuseful in producing a porous coating layer of the invention.

[0087] Polymer(s) useful for forming the porous coating layer should beones that are biostable, biocompatible, particularly during insertion orimplantation of the device into the body and avoids irritation to bodytissue. Examples of such polymers include, but not limited to,polyurethanes, polyisobutylene and its copolymers, silicones, andpolyesters. Other suitable polymers include polyolefins,polyisobutylene, ethylene-alphaolefin copolymers, acrylic polymers andcopolymers, vinyl halide polymers and copolymers such as polyvinylchloride, polyvinyl ethers such as polyvinyl methyl ether,polyvinylidene halides such as polyvinylidene fluoride andpolyvinylidene chloride, polyacrylonitrile, polyvinyl ketones, polyvinylaromatics such as polystyrene, polyvinyl esters such as polyvinylacetate; copolymers of vinyl monomers, copolymers of vinyl monomers andolefins such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, ethylene-vinyl acetatecopolymers, polyamides such as Nylon 66 and polycaprolactone, alkydresins, polycarbonates, polyoxyethylenes, polyimides, polyethers, epoxyresins, polyurethanes, rayon-triacetate, cellulose, cellulose acetate,cellulose butyrate, cellulose acetate butyrate, cellophane, cellulosenitrate, cellulose propionate, cellulose ethers, carboxymethylcellulose, collagens, chitins, polylactic acid, polyglycolic acid, andpolylactic acid-polyethylene oxide copolymers. Since the polymer isbeing applied to a part of the medical device which undergoes mechanicalchallenges, e.g. expansion and contraction, the polymers are preferablyselected from elastomeric polymers such as silicones (e.g. polysiloxanesand substituted polysiloxanes), polyurethanes, thermoplastic elastomers,ethylene vinyl acetate copolymers, polyolefin elastomers, and EPDMrubbers. The polymer is selected to allow the coating to better adhereto the surface of the expandable portion of the medical device when itis subjected to forces or stress. Furthermore, although the porouscoating layer can be formed by using a single type of polymer, variouscombinations of polymers can be employed.

[0088] The elutable particulate materials which can be incorporated intothe polymer include, but not limited to, polyethylene oxide,polyethylene glycol, polyethylene oxide/polypropylene oxide copolymers,polyhydroxyethyl methacrylate, polyvinylpyrrolidone, polyacrylamide andits copolymers, salts, e.g., sodium chloride, sugars, and elutablebiologically active materials such as heparin. The amount of elutableparticulate material that is incorporated into the polymer should rangefrom about 20% to 90% by weight of the porous coating layer.Furthermore, to increase the porosity of the coating layer applied tothe end sections of the surface, a larger amount of the elutableparticulate material can be used to form the porous coating layer at theend sections than are used to form the porous coating layer at themiddle section. For example, the amount of the elutable particulatematerial may be from about 0% to about 40% for the porous coating layercovering the middle section, and about 50% to 90for the porous coatinglayer covering at the end sections. Also, a more porous coating layercan be realized by using larger average particle size of the elutablematerial. For example, the particles may have an average particle sizefrom 60-100 microns for porous coating layer covering the end sectionsand from 0 to about 30 microns for the porous coating layer coveringmiddle section.

[0089] The solvent that is used to form the mixture or slurry of polymerand elutable particulate materials include ones which can dissolve thepolymer into solution and do not alter or adversely impact thetherapeutic properties of the biologically active material employed.Examples of useful solvents for silicone include tetrahydrofuran (THF),chloroform and dichloromethane. The composition of polymer and elutableparticulate material can be applied to the portion of the medical devicein a variety of ways. For example, the composition can be spray-coatedonto the device or the device can be dipped into the composition. One ofskill in the art would be aware of methods for applying the coating tothe device.

[0090] The thickness of the porous coating layer can range from about 25μm to 0.5 mm. Preferably, the thickness is about 30 μm to 100 μm. Afterthe composition is applied to the device, it should be cured to producea polymer containing the particulate material and to evaporate thesolvent.

[0091] To elute the particulate material from the polymer, a solvent isused. The device can be soaked in the solvent to elute the particulatematerials. Other methods of eluting the particulate are apparent tothose skilled in the art. The choice of the solvent depends upon thesolubility of the elutable particulate material in that solvent. Forinstance, for water-soluble particulate materials such as heparin, watercan be used. For elutable particulate materials that can be dissolved inorganic solvents, such organic solvents can be used. Examples ofsuitable solvents, without limitation, include ethanol, dimethylsulfoxide, etc.

[0092] Another example of a method for preparing a porous coating is acatalyst-free vapor deposition of a coating composition comprising apolyamide, parylene or a parylene derivative. See U.S. Pat. No.6,299,604 to Ragheb et al., which is incorporated herein by reference.

[0093] In another embodiment of the present invention, the surfaceincluding the end sections and middle section are covered with a sameporous coating layer composition, but the porous coating layer isthicker at the end sections than at the middle section. For example, aporous coating layer is applied to the entire surface, and then anotherporous coating layer is applied to the end sections while the middlesection is covered by a sheath. The thickness of the porous coatinglayer at the end sections may be from about 80 μm to about 0.5 mm, andthat at the middle section maybe from about 10 μm to 40 μm. Since thereis more porous coating at the end sections, the end sections of theouter surface should have a greater capacity to carry or contain abiologically active material.

[0094] 2.2 The End Sections with Greater Affinity for the BiologicallyActive Material

[0095] In another embodiment of the medical device of the presentinvention, the end sections of the outer surface have a greater affinityfor the biologically active material than the middle section. Inparticular, the end sections comprise a first matrix material and themiddle section comprises a second matrix material. The first matrixmaterial has a greater affinity for the biologically active material ofinterest than the second matrix material so that the end sections cancarry or contain a larger amount of the biologically active material perunit length of the outer surface than the middle section. The endsections and the middle section of the outer surface may be formed fromthe first matrix material and the second matrix material, respectively.Preferably, the end sections of the outer surface and the middle sectionof the outer surface are formed of another material and then are coveredwith a coating comprising each of the matrix materials.

[0096] Generally, when a biologically active material used is ahydrophilic, e.g., heparin, then a matrix material comprising a morehydrophilic material has a greater affinity for the biologically activematerial than another matrix material that is less hydrophilic. When abiologically active material used is a hydrophobic, e.g., paclitaxel,actinomycin, sirolimus (RAPAMYCIN), tacrolimus, everolimus, anddexamethasone, then a matrix material that is more hydrophobic has agreater affinity for the biologically active material than anothermatrix material that is less hydrophobic.

[0097] Examples of suitable hydrophobic polymers include, but notlimited to, polyolefins, such as polyethylene, polypropylene,poly(1-butene), poly(2-butene), poly(1-pentene), poly(2-pentene),poly(3-methyl-1-pentene), poly(4-methyl-1-pentene), poly(isoprene),poly(4-methyl-1-pentene), ethylene-propylene copolymers,ethylene-propylene-hexadiene copolymers, ethylene-vinyl acetatecopolymers, blends of two or more polyolefins and random and blockcopolymers prepared from two or more different unsaturated monomers;styrene polymers, such as poly(styrene), poly(2-methylstyrene),styrene-acrylonitrile copolymers having less than about 20mole-percentacrylonitrile, and styrene-2,2,3,3,-tetrafluoropropyl methacrylatecopolymers; halogenated hydrocarbon polymers, such aspoly(chlorotrifluoroethylene),chlorotrifluoroethylene-tetrafluoroethylene copolymers,poly(hexafluoropropylene), poly(tetrafluoroethylene),tetrafluoroethylene, tetrafluoroethylene-ethylene copolymers,poly(trifluoroethylene), poly(vinyl fluoride), and poly(vinylidenefluoride); vinyl polymers, such as poly(vinyl butyrate), poly(vinyldecanoate), poly(vinyl dodecanoate), poly(vinyl hexadecanoate),poly(vinyl hexanoate), poly(vinyl propionate), poly(vinyl octanoate),poly(heptafluoroisopropoxyethylene),poly(heptafluoroisopropoxypropylene), and poly(methacrylonitrile);acrylic polymers, such as poly(n-butyl acetate), poly(ethyl acrylate),poly(1-chlorodifluoromethyl)tetrafluoroethyl acrylate, polydi(chlorofluoromethyl)fluoromethyl acrylate,poly(1,1-dihydroheptafluorobutyl acrylate),poly(1,1-dihydropentafluoroisopropyl acrylate),poly(1,1-dihydropentadecafluorooctyl acrylate),poly(heptafluoroisopropyl acrylate), poly5-(heptafluoroisopropoxy)pentyl acrylate, poly11-(heptafluoroisopropoxy)undecyl acrylate, poly2-(heptafluoropropoxy)ethyl acrylate, and poly(nonafluoroisobutylacrylate); methacrylic polymers, such as poly(benzyl methacrylate),poly(n-butyl methacrylate), poly(isobutyl methacrylate), poly(t-butylmethacrylate), poly(t-butylaminoethyl methacrylate), poly(dodecylmethacrylate), poly(ethyl methacrylate), poly(2-ethylhexylmethacrylate), poly(n-hexyl methacrylate), poly(phenyl methacrylate),poly(n-propyl methacrylate), poly(octadecyl methacrylate),poly(1,1-dihydropentadecafluorooctyl methacrylate),poly(heptafluoroisopropyl methacrylate), poly(heptadecafluorooctylmethacrylate), poly(1-hydrotetrafluoroethyl methacrylate),poly(1,1-dihydrotetrafluoropropyl methacrylate),poly(1-hydrohexafluoroisopropyl methacrylate), andpoly(t-nonafluorobutyl methacrylate); polyesters, such a poly(ethyleneterephthalate) and poly(butylene terephthalate); condensation typepolymers such as and polyurethanes and siloxane-urethane copolymers;polyorganosiloxanes, i.e., polymeric materials characterized byrepeating siloxane groups, represented by R_(a) SiO_(4-a/2), where R isa monovalent substituted or unsubstituted hydrocarbon radical and thevalue of a is 1or 2; and naturally occurring hydrophobic polymers suchas rubber.

[0098] Examples of suitable hydrophilic monomer include, but not limitedto, (meth)acrylic acid, or alkaline metal or ammonium salts thereof;(meth)acrylamide; (meth)acrylonitrile; those polymers to whichunsaturated dibasic, such as maleic acid and fumaric acid or half estersof these unsaturated dibasic acids, or alkaline metal or ammonium saltsof these dibasic adds or half esters, is added; those polymers to whichunsaturated sulfonic, such as 2-acrylamido-2-methylpropanesulfonic,2-(meth)acryloylethanesulfonic acid, or alkaline metal or ammonium saltsthereof, is added; and 2-hydroxyethyl (meth)acrylate and 2-hydroxypropyl(meth)acrylate.

[0099] Polyvinyl alcohol is also an example of hydrophilic polymer.Polyvinyl alcohol may contain a plurality of hydrophilic groups such ashydroxyl, amido, carboxyl, amino, ammonium or sulfonyl (—SO₃).Hydrophilic polymers also include, but are not limited to, starch,polysaccharides and related cellulosic polymers; polyalkylene glycolsand oxides such as the polyethylene oxides; polymerized ethylenicallyunsaturated carboxylic acids such as acrylic, mathacrylic and maleicacids and partial esters derived from these acids and polyhydricalcohols such as the alkylene glycols; homopolymers and copolymersderived from acrylamide; and homopolymers and copolymers ofvinylpyrrolidone.

[0100] The first matrix material and the second matrix material may beprepared using either a hydrophilic polymer or a hydrophobic polymer, ora blend of a hydrophobic polymer and a hydrophilic polymer in a chosenratio. For example, when the biologically active material ishydrophilic, then the first matrix material may be prepared by blendingfrom about 55% to about 100% hydrophilic polymer and from about 45% toabout 0% hydrophobic polymer; and the second matrix material may beprepared by blending from about 55% to about 100% hydrophobic polymerand from about 45% to about 0% hydrophilic polymer. The first matrixmaterial contains a greater amount of the hydrophillic polymer than thesecond matrix material. When the biologically active material ishydrophobic, then the first matrix material may be prepared by blendingfrom about 55% to about 95% hydrophobic polymer and from about 45% toabout 5% hydrophilic polymer; and the second matrix material may beprepared by blending from about 55% to about 95% hydrophilic polymer andfrom about 45% to about 5% hydrophobic polymer. The first matrixmaterial contains a greater amount of the hydrophobic polymer than thesecond matrix material.

[0101] Again, the outer surface of the medical device of the presentinvention is, covered with each matrix material, i.e., the end sectionswith a first matrix material and the middle section with a second matrixmaterial. A first matrix material composition may be prepared andapplied by any method to a surface of a medical device to form acoating, such as spraying, dipping, rolling, and electrostaticdeposition. Likewise, a second matrix material composition may beprepared and applied by such methods. The first matrix materialcomposition may be applied to the end sections of the outer surfacewhile the middle section is covered to prevent coating the middlesection with the first matrix material. Then the second matrix materialcomposition may be applied to the middle section while the end sectionsare covered. In another embodiment, the second material composition maybe applied to the entire outer surface including the middle section andthe end sections, then the first matrix material composition may beapplied to the end sections while the middle section is covered.

[0102] After the matrix material compositions are applied to the outersurface, the surface should be cured to produce matrix materialcoatings. The thickness of the matrix material coating can range fromabout 25 μm to about 0.5 mm. Preferably, the thickness is about 30 μm to100 μm.

[0103] 2.3 The End Sections with Greater Amount of Chemical LinkingMaterial to Carry or Contain the Biologically Active Material

[0104] In yet another embodiment of the present invention, the capacityof the end sections of the outer surface for carrying or containing abiologically active material can be increased relative to that of themiddle section by using an increased amount of chemical linking materialto link the biologically active material to the end sections of theouter surface. Specifically, the middle section and end sections of theouter surface are covered with a chemical linking material, and the endsections carry or contain a larger amount of the linking material perunit length of outer surface than the middle section. The chemicallinking material allows the biologically active material to attach tothe outer surface. “Linking materials” may be any material which can becoupled to a biologically active material by any bond that are known inthe relevant art including, but not limited to, Van der Waals force,ionic bond, covalent bond, hydrogen bond or chemical cross-linking.

[0105] For example, U.S. Pat. No. ,356,433 o Rowland et al., disclosesthat polysaccharides can be immobilized onto metallic surfaces byapplying an organosilane coating with amine functionality and thenapplying a polysaccharide using carbodiimide as a coupling agent. In thepresent invention, if the organosilane with amine functionality is usedas a linking material, the amount of this material per unit length ofthe outer surface at the end sections is greater than that at the middlesection. In that way, a larger amount of a polysaccharide, which is abiologically active material, can be coupled to the end sections.

[0106] Also, U.S. Pat. No. ,336,518 to Narayanan et al. discloses that apolysaccharide can be immobilized on a surface by applying a coat ofheptafluorobutylmethacrylate (HFBMA) by radiofrequency (RF) plasmadeposition, creating functional groups on the surface by RF plasma withwater vapor, and then applying the polysaccharide using carbodiimide. Inthe present invention, a larger amount of HFBMA, a linking material, isapplied to the end sections so that larger amount of a polysaccharide, abiologically active material can be coupled to the HFBMA.

3. Radially Asymmetric Medical Devices Having Increased Capacity forCarrying or Containing a Biologically Active Material

[0107] 3.1 Medical Devices Having Non-Structural Elements Located in aRadially Asymmetric Distribution

[0108] As explained above, one way to increase the capacity for carryingor containing a biologically active material of the medical device is toincrease available surface area. In one embodiment of the medical deviceof the invention, the available surface area is increased in radiallyasymmetric manner along the entire outer surface, instead of only at theend sections. One such embodiment where the surface area is increased ina radially asymmetric manner by adding non-structural elements to theouter surface (as to non-structural elements, see section 1.3. Forexample, only a rectangular portion of the outer surface has thenon-structural elements. Such rectangular portion may be parallel tolongitudinal axis of the tubular portion and may have the same length asthat of the tubular portion. The rectangular portion is preferably fromabout 25% to about 75% of the entire outer surface. Please see section1.3 as to a method for delivering a biologically active material to bodytissue using such medical device.

3.2 Medical Device Having Radially Asymmetric Increased AvailableSurface Area or Affinity

[0109] Another embodiment of the medical device of the inventioncomprises a tubular portion comprising struts and having an outersurface. A portion of the outer surface has increased available surfaceor affinity for the biologically active material in such a way that theavailable surface area or affinity for the biologically active materialis radially asymmetric. Please see prior section (section 3.1) as toexamples of radially asymmetric distributions. Increased availablesurface area or increased affinity to the biologically active materialcan be achieved as explained in the prior sections (sections 2.1 and2.2). Please see section 1.3 as to a method for delivering abiologically active material to body tissue using such medical device.

4. Suitable Medical Devices

[0110] The medical devices of the present invention are insertable intothe body of a patient. Namely, at least a portion of such medicaldevices may be temporarily inserted into or semi-permanently orpermanently implanted in the body of a patient. Preferably, the medicaldevices of the present invention comprise a tubular portion which isinsertable into the body of a patient. The tubular portion of themedical device need not to be completely cylindrical. For instance, thecross-section of the tubular portion can be any shape, such as arectangle, a triangle, etc., not just a circle.

[0111] The medical devices suitable for the present invention include,but are not limited to, stents, surgical staples, catheters, such ascentral venous catheters and arterial catheters, guidewires, balloons,filters (e.g., vena cava filters), cannulas, cardiac pacemaker leads orlead tips, cardiac defibrillator leads or lead tips, implantablevascular access ports, stent grafts, vascular grafts or other grafts,interluminal paving system, intra-aortic balloon pumps, heart valves,cardiovascular sutures, total artificial hearts and ventricular assistpumps.

[0112] Medical devices which are particularly suitable for the presentinvention include any kind of stent for medical purposes, which areknown to the skilled artisan. Suitable stents include, for example,vascular stents such as self-expanding stents and balloon expandablestents. Examples of self-expanding stents useful in the presentinvention are illustrated in U.S. Pat. Nos. 4,655,771 and 4,954,126issued to Wallsten and U.S. Pat. No. 5,061,275 issued to Wallsten et al.Examples of appropriate balloon-expandable stents are shown in U.S. Pat.No. 4,733,665 issued to Palmaz, U.S. Pat. No. 4,800,882 issued toGianturco, U.S. Pat. No. 4,886,062 issued to Wiktor and U.S. Pat. No.5,449,373 issued to Pinchasik et al. A bifurcated stent is also includedamong the medical devices suitable for the present invention.

[0113] The medical devices suitable for the present invention may befabricated from polymeric and/or metallic materials. Examples of suchpolymeric materials include polyurethane and its copolymers, siliconeand its copolymers, ethylene vinyl-acetate, poly(ethyleneterephthalate), thermoplastic elastomer, polyvinyl chloride,polyolephines, cellulosics, polyamides, polyesters, polysulfones,polytetrafluoroethylenes, acrylonitrile butadiene styrene copolymers,acrylics, polyactic acid, polyclycolic acid, polycaprolactone,polyacetal, poly(lactic acid), polylactic acid-polyethylene oxidecopolymers, polycarbonate cellulose, collagen and chitins. Examples ofsuitable metallic materials include metals and alloys based on titanium(e.g., nitinol, nickel titanium alloys, thermo-memory alloy materials),stainless steel, platinum, tantalum, nickel-chrome, certain cobaltalloys including cobalt-chromium-nickel alloys (e.g., Elgiloy® andPhynox®) and gold/platinum alloy. Metallic materials also include cladcomposite filaments, such as those disclosed in WO 94/16646.

[0114] The medical devices suitable for the present invention also havean outer surface, and the outer surface has end sections and middlesection. The term “outer surface” refers to a surface of the medicaldevices which are to be exposed to the body tissue. For example, thetubular structure shown in FIG. 20 is a simplified view of a stent 40.The outer surface of the stent is the surface that is in direct contactwith the body tissue when the device is inserted into the body. In thecase that the medical device is a stent 40 comprised of struts 42 asshown in FIG. 19, the “outer surface” of the stent refers to thesurfaces of the struts which are to directly contact with the body lumenor tissue.

[0115] The term “end section” of the outer surface refers to that partof the surface which extends from an end or edge of the tubular portionup to about 25%, preferably from about 3% to about 20% of the entirelength of the outer surface. For example, when the medical device is astent 40 as shown in FIG. 19 or 20, the end section 46 of the outersurface is a ring-shape portion extending from the edge of the outersurface of stent having length e, which is up to 25% of the entirelength a of the outer surface of stent. In FIGS. 19 and 20, the endsections 46 are shown as the shaded portions.

[0116] The term “middle section” refers to the remainder of the outersurface that is surrounded by the end sections as defined above. Forexample, in FIG. 19 or 20, the middle section 44 is a ring-shape portionhaving length m, which is surrounded by the end sections.

5. Applying Biologically Active Material to the Outer Surface

[0117] As discussed earlier, the biologically active material can beapplied to the embodiments described in sections 2.1 to 2.3 when thedevice is manufactured or afterwards by a medical professional shortlybefore the device is inserted into a patient. The biologically activematerial may be applied to the outer surface of the device obtained asin sections 1.1-1.3, 2.1-2.3 and 3.1-3.2, alone or in conjunction withother materials, such as a polymeric material. For example, in theembodiment where the end sections have a greater available surface areaper unit length of the outer surface than the middle section, thebiologically active material can be applied to the outer surface in acoating composition containing the biologically active material and apolymeric material. Specifically, a coating composition of biologicallyactive material and polymeric material can be prepared and then appliedto the outer surface. However, the biologically active material alonecan also be applied to the outer surface of this embodiment.

[0118] In the embodiments where a portion of the outer surface has agreater affinity for the biologically active material or where a portionof the outer surface contains more chemical liking material, thebiologically active material is preferably applied alone to the outersurface. For instance, in the embodiment having a matrix material withgreater affinity for the biologically active material in a portion ofthe outer surface, the biologically active material can be applied tothe matrix material coatings on the outer surface. However, thebiologically active material can also be applied to the material alongwith a polymeric material. Also, the biologically active material can beincorporated into the matrix material coating compositions to formmatrix material coatings already containing the biologically activematerial.

[0119] 5.1 Coating Compositions and Coating Layers

[0120] The coating compositions suitable for the present invention canbe applied by any method to a surface of a medical device to form acoating. Examples of such methods are spraying, dipping, rolling,electrostatic deposition and all modem chemical ways of immobilizationof bio-molecules to surfaces.

[0121] The coating composition used in the present invention may be asolution of a biologically active material in an aqueous or organicsolvent. Such coating composition may be applied to a surface, and thesolvent may be evaporated. A biologically active material solution maybe used when the tubular portion of the medical device has end sectionshaving increased surface area or increased affinity as explained above,especially when the end sections are porous.

[0122] Furthermore, coating compositions useful for the presentinvention may include a polymeric material and optionally a biologicallyactive material dispersed or dissolved in a solvent suitable for themedical device which is known to the skilled artisan. The solvents usedto prepare coating compositions include ones which can dissolve thepolymeric material into solution and do not alter or adversely impactthe therapeutic properties of the biologically active material employed.For example, useful solvents for silicone include tetrahydrofuran (THF),chloroform, toluene, acetone, isooctane, 1,1,1-trichloroethane,dichloromethane, and a mixture thereof.

[0123] A coating of a medical device of the present invention mayconsist of various kinds of combination of multiple coating layers. Forexample, the first layer and the second layer may contain differentbiologically active materials. Alternatively, the first layer and thesecond layer may contain an identical biologically active materialhaving different concentrations. In one embodiment, either of the firstlayer or the second layer may be free of biologically active material.For example, when the biologically active solution is applied onto asurface and dried (the first layer), a coating composition free of abiologically active material (the second layer) can be applied over thedried biologically active material.

[0124] The polymeric material should be a material that is biocompatibleand avoids irritation to body tissue. Examples of the polymericmaterials used in the coating composition of the present inventioninclude, but not limited to, polycarboxylic acids, cellulosic polymers,including cellulose acetate and cellulose nitrate, gelatin,polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyanhydridesincluding maleic anhydride polymers, polyamides, polyvinyl alcohols,copolymers of vinyl monomers such as EVA, polyvinyl ethers, polyvinylaromatics, polyethylene oxides, glycosaminoglycans, polysaccharides,polyesters including polyethylene terephthalate, polyacrylamides,polyethers, polyether sulfone, polycarbonate, polyalkylenes includingpolypropylene, polyethylene and high molecular weight polyethylene,halogenated polyalkylenes including polytetrafluoroethylene,polyurethanes, polyorthoesters, proteins, polypeptides, silicones,siloxane polymers, polylactic acid, polyglycolic acid, polycaprolactone,polyhydroxybutyrate valerate, styrene-isobutylene copolymers and blendsand copolymers thereof. Also, other examples of such polymers includepolyurethane (BAYHDROL®, etc.) fibrin, collagen and derivatives thereof,polysaccharides such as celluloses, starches, dextrans, alginates andderivatives, hyaluronic acid, and squalene. Further examples of thepolymeric materials used in the coating composition of the presentinvention include other polymers which can be used include ones that canbe dissolved and cured or polymerized on the medical device or polymershaving relatively low melting points that can be blended withbiologically active materials. Additional suitable polymers include,thermoplastic elastomers in general, polyolefins, polyisobutylene,ethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinylhalide polymers and copolymers such as polyvinyl chloride, polyvinylethers such as polyvinyl methyl ether, polyvinylidene halides such aspolyvinylidene fluoride and polyvinylidene chloride, polyacrylonitrile,polyvinyl ketones, polyvinyl aromatics such as polystyrene, polyvinylesters such as polyvinyl acetate, copolymers of vinyl monomers,copolymers of vinyl monomers and olefins such as ethylene-methylmethacrylate copolymers, acrylonitrile-styrene copolymers, ABS(acrylonitrile-butadiene-styrene) resins, ethylene-vinyl acetatecopolymers, polyamides such as Nylon 66 and polycaprolactone, alkydresins, polycarbonates, polyoxymethylenes, polyimides, epoxy resins,rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate,cellulose acetate butyrate, cellophane, cellulose nitrate, cellulosepropionate, cellulose ethers, carboxymethyl cellulose, collagens,chitins, polylactic acid, polyglycolic acid, polylacticacid-polyethylene oxide copolymers, EPDM (etylene-propylene-diene)rubbers, fluorosilicones, polyethylene glycol, polysaccharides,phospholipids, and combinations of the foregoing.

[0125] Preferred is polyacrylic acid, available as HYDROPLUS® (BostonScientific Corporation, Natick, Mass.), and described in U.S. Pat. No.5,091,205, the disclosure of which is hereby incorporated herein byreference. In a most preferred embodiment of the invention, the polymeris a copolymer of polylactic acid and polycaprolactone.

[0126] More preferably for medical devices which undergo mechanicalchallenges, e.g. expansion and contraction, the polymeric materialsshould be selected from elastomeric polymers such as silicones (e.g.polysiloxanes and substituted polysiloxanes), polyurethanes,thermoplastic elastomers, ethylene vinyl acetate copolymers, polyolefinelastomers, and EPDM rubbers. Because of the elastic nature of thesepolymers, the coating composition adheres better to the surface of themedical device when the device is subjected to forces, stress ormechanical challenge.

[0127] A controlled-release coating of a biologically active materialmay be prepared by a coating composition comprising an appropriatehydrophobic polymer. For example, a controlled-release coating maycomprise a coating layer containing a biologically active material and atop coating layer comprising a hydrophobic polymer. Also, acontrolled-release coating may be prepared from a coating compositioncontaining a mixture of a hydrophobic polymer and a biologically activematerial.

[0128] The amount of the polymeric material present in the coatings canvary based on the application for the medical device. One skilled in theart is aware of how to determine the desired amount and type ofpolymeric material used in the coating. The thickness of the coating isnot limited, but generally ranges from about 25 μm to about 0.5 mm.Preferably, the thickness is about 30 μm to 100 μm.

[0129] 5.2 Suitable Biologically Active Material

[0130] The term “biologically active material” encompasses therapeuticagents, such as drugs, and also genetic materials and biologicalmaterials. The genetic materials mean DNA or RNA, including, withoutlimitation, of DNA/RNA encoding a useful protein stated below,anti-sense DNA/RNA, intended to be inserted into a human body includingviral vectors and non-viral vectors. Examples of DNA suitable for thepresent invention include DNA encoding:

[0131] anti-sense RNA;

[0132] tRNA or rRNA to replace defective or deficient endogenousmolecules;

[0133] angiogenic factors including growth factors, such as acidic andbasic fibroblast growth factors, vascular endothelial growth factor,epidermal growth factor, transforming growth factor α and β,platelet-derived endothelial growth factor, platelet-derived growthfactor, tumor necrosis factor a, hepatocyte growth factor and insulinlike growth factor;

[0134] cell ccle inhibitors including CD inhibitors;

[0135] thymidine kinase (“TK”) and other agents useful for interferingwith cell proliferation; and

[0136] the family of bone morphogenic proteins (“BMP's”) as explainedbelow.

[0137] Viral vectors include adenoviruses, gutted adenoviruses,adeno-associated virus, retroviruses, alpha virus (Semliki Forest,Sindbis, etc.), lentiviruses, herpes simplex virus, ex vivo modifiedcells (e.g., stem cells, fibroblasts, myoblasts, satellite cells,pericytes, cardiomyocytes, sketetal myocytes, macrophage), replicationcompetent viruses (e.g., ONYX-015), and hybrid vectors. Non-viralvectors include artificial chromosomes and mini-chromosomes, plasmid DNAvectors (e.g., PCOR), cationic polymers (e.g., polyethyleneimine,polyethyleneimine (PEI)) graft copolymers (e.g., polyether-PEI andpolyethylene oxide-PEI), neutral polymers PVP, SP 1017 (SUPRATEK),lipids or lipoplexes, nanoparticles and microparticles with and withouttargeting sequences such as the protein transduction domain (PTD).

[0138] The biological materials include cells, yeasts, bacteria,proteins, peptides, cytokines and hormones. Examples for peptides andproteins include growth factors (FGF, FGF-1, FGF-2, VEGF, EndotherialMitogenic Growth Factors, and epidermal growth factors, transforminggrowth factor a and P, platelet derived endothelial growth factor,platelet derived growth factor, tumor necrosis factor a, hepatocytegrowth factor and insulin like growth factor), transcription factors,proteinkinases, CD inhibitors, thymidine kinase, and bone morphogenicproteins (BMP's), such as BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1),BMP-7(OP-1), BMP-8. BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14,BMP-15, and BMP-16. Currently preferred BMP's are BMP-2, BMP-3, BMP-4,BMP-5, BMP-6, BMP-7. Alternatively or in addition, molecules capable ofinducing an upstream or downstream effect of a BMP can be provided. Suchmolecules include any of the “hedgehog” proteins, or the DNA's encodingthem. These dimeric proteins can be provided as homodimers,heterodimers, or combinations thereof, alone or together with othermolecules. Cells can be of human origin (autologous or allogeneic) orfrom an animal source (xenogeneic), genetically engineered, if desired,to deliver proteins of interest at the transplant site. The deliverymedia can be formulated as needed to maintain cell function andviability. Cells include whole bone marrow, bone marrow derivedmono-nuclear cells, progenitor cells (e.g., endothelial progentitorcells), stem cells (e.g., mesenchymal, hematopoietic, neuronal),pluripotent stem cells, fibroblasts, macrophage, and satellite cells.

[0139] Biologically active material also includes non-genetictherapeutic agents, such as:

[0140] anti-thrombogenic agents such as heparin, heparin derivatives,urokinase, and PPack (dextrophenylalanine proline argininechloromethylketone);

[0141] anti-proliferative agents such as enoxaprin, angiopeptin, ormonoclonal antibodies capable of blocking smooth muscle cellproliferation, hirudin, and acetylsalicylic acid, tacrolimus,everolimus, amlodipine and doxazosin;

[0142] anti-inflammatory agents such as glucocorticoids, betamethasone,dexamethasone, prednisolone, corticosterone, budesonide, estrogen,sulfasalazine, rosiglitazone, mycophenolic acid, and mesalamine;

[0143] immunosuppressants such as sirolimus (RAPAMYCIN), tacrolimus,everolimus and dexamethasone;

[0144] antineoplastic/antiproliferative/anti-miotic agents such aspaclitaxel, 5-fluorouracil, cisplatin, vinblastine, cladribine,vincristine, epothilones, methotrexate, azathioprine, halofuginone,adriamycin, actinomycin and mutamycin; endostatin, angiostatin andthymidine kinase inhibitors, and its analogs or derivatives;

[0145] anesthetic agents such as lidocaine, bupivacaine, andropivacaine;

[0146] anti-coagulants such as D-Phe-Pro-Arg chloromethyl keton, an RGDpeptide-containing compound, heparin, antithrombin compounds, plateletreceptor antagonists, anti-thrombin anticodies, anti-platelet receptorantibodies, aspirin (aspirin is also classified as an analgesic,antipyretic and anti-inflammatory drug), dipyridamole, protamine,hirudin, prostaglandin inhibitors, platelet inhibitors and antiplateletagents such as trapidil or liprostin, tick antiplatelet peptides;

[0147] DNA demethylating drugs such as 5-azacytidine, which is alsocategorized as a RNA or DNA metabolite that inhibit cell growth andinduce apoptosis in certain cancer cells;

[0148] vascular cell growth promotors such as growth factors, VascularEndothelial Growth Factors (FEGF, all types including VEGF-2), growthfactor receptors, transcriptional activators, and translationalpromotors;

[0149] vascular cell growth inhibitors such as antiproliferative agents,growth factor inhibitors, growth factor receptor antagonists,transcriptional repressors, translational repressors, replicationinhibitors, inhibitory antibodies, antibodies directed against growthfactors, bifunctional molecules consisting of a growth factor and acytotoxin, bifunctional molecules consisting of an antibody and acytotoxin;

[0150] cholesterol-lowering agents; vasodilating agents; and agentswhich interfere with endogenous vasoactive mechanisms;

[0151] anti-oxidants, such as probucol;

[0152] antibiotic agents, such as penicillin, cefoxitin, oxacillin,tobranycin;

[0153] angiogenic substances, such as acidic and basic fibrobrast growthfactors, estrogen including estradiol (E2), estriol (E3) and 17-BetaEstradiol;

[0154] drugs for heart failure, such as digoxin, beta-blockers,angiotensin-converting enzyme (ACE) inhibitors including captopril andenalopril, statins and related compounds; and

[0155] macrolides such as sirolimus or everolimus.

[0156] Also, the biologically active materials of the present inventioninclude nitric oxide adducts, which prevent and/or treat adverse effectsassociated with use of a medical device in a patient, such as restenosisand damaged blood vessel surface. Typical nitric oxide adducts includenitroglycerin, sodium nitroprusside, S-nitroso-proteins,S-nitroso-thiols, long carbon-chain lipophilic S-nitrosothiols,S-nitrosodithiols, iron-nitrosyl compounds, thionitrates, thionitrites,sydnonimines, furoxans, organic nitrates, and nitrosated amino acids,preferably mono-or poly-nitrosylated proteins, particularlypolynitrosated albumin or polymers or aggregates thereof. The albumin ispreferably human or bovine, including humanized bovine serum albumin.Such nitric oxide adducts are disclosed in U.S. Pat. No. 6,087,479 toStamler et al. which is incorporated herein by reference.

[0157] In addition, biologically active materials includeanti-proliferative drugs such as steroids, vitamins, andrestenosis-inhibiting agents. Preferred restenosis-inhibiting agentsinclude microtubule stabilizing agents such as Taxol, paclitaxel,paclitaxel analogues, derivatives, and mixtures thereof. For example,derivatives suitable for use in the present invention include2′-succinyl-taxol, 2′-succinyl-taxol triethanolamine, 2′-glutaryl-taxol,2′-glutaryl-taxol triethanolamine salt, 2′-O-ester withN-(dimethylaminoethyl) glutamine, and 2′-O-ester withN-(dimethylaminoethyl) glutamide hydrochloride salt. Other preferredbiologically active materials include nitroglycerin, nitrous oxides,nitric oxides, antibiotics, aspirins, digitalis, estrogen derivativessuch as estradiol and glycosides. A biologically active material may beencapsulated in micro-capsules by the known methods.

[0158] 5.3 Medical Devices with End Sections that Carry or Contain aGreater Amount of Biologically Active Material than the Middle Section

[0159] In another embodiment of the invention, a more uniformrelease-profile for a biologically active material along the length ofthe outer surface of the medical device may be achieved by preparing amedical device having end sections that carry or contain a greateramount of a biologically active material than the middle section.

[0160] In section 2, supra, the medical devices of the present inventionhaving end sections that have increased capacity for carrying orcontaining a biologically active material were explained. When a coatingcomposition comprising the biologically active material is applied tosuch medical devices by a conventional method, such as spraying,dipping, rolling, and electrostatic deposition, the end sections willcarry or contain a greater amount of the biologically active materialper unit length of the outer surface than the middle section of theouter surface.

[0161] However, greater amounts of biologically active material at theend sections can also be achieved by controlling the amount of thebiologically active material that is applied to the middle and endsections. For instance, additional coating composition containing abiologically active material can be applied to the end sections so thatsuch sections have a thicker coating and hence contain more biologicallyactive material. A method for preparing such medical device comprises,for example, applying a first coating composition containing abiologically active material to the end sections and a middle section ofan outer surface, placing a cover over the middle section, applying moreof the first coating composition or second coating composition to theend sections of the outer surface. The second coating composition maycontain the same biologically active material as the first coatingcomposition having the same or different concentration or may contain adifferent biologically active material.

[0162] Another example of a method useful in allowing more biologicallyactive material to the end sections relative to the middle sectioninvolves covering the middle section. In particular, a coatingcomposition containing the desired biologically active material isapplied to the middle section and end sections. The middle section isthen covered by a sheath or mesh. Such covering can be achieved also bymasking using photolithography techniques. Additional coatingcomposition is then applied to the end sections. The covering preventssuch additional coating composition from being applied to the middlesection so that the end sections will contain relatively morebiologically active material.

[0163] In yet another embodiment of the medical device of the presentinvention, a greater amount of the biologically active material can beapplied to the end sections by applying coating compositions havingdifferent concentration of the first biologically active material to themiddle and end sections. For example, applying a coating compositioncontaining a first concentration of a biologically active material isapplied to the end sections while the middle section is covered.Thereafter, a second coating composition having a second concentrationof the biologically active material, which is smaller than the firstconcentration, to the middle section. The sections may be covered usingsheaths or masking as explained above.

[0164] 5.4 Medical Device Comprising a Biologically Active Material in aRadially Asymmetric Distribution

[0165] Yet another embodiment of the medical device of the inventionachieves a greater amount of release of a biologically active materialto a necessary body tissue. Such medical device comprises an outersurface comprising the biologically active material in a radiallyasymmetric distribution. For example, a rectangular portion of the outersurface has a greater amount of the biologically active material thanthe rest of the outer surface. When the medical device comprises atubular portion, the rectangular portion may be parallel to longitudinalaxis of the tubular portion. The rectangular portion may be the samelength as that of the tubular portion. A greater amount of thebiologically active material can be distributed to a rectangular portionusing any of the manners used to distribute a greater amount of thebiologically active material to the end sections (see section 5.3,supra).

6. Barrier Layer Over the Middle Section

[0166] In yet another embodiment, there is a barrier layer placed overthe middle section of the outer surface, so that the end sections of theouter surface are allowed to release greater amounts of the biologicallyactive material relative to the middle section. The middle and endsections are covered with a coating composition containing biologicallyactive material. A covering or barrier layer is then placed over themiddle section to limit the release of the biologically active material.In this way, the release ratio of biologically active material from theend sections is relatively greater than from the middle section.

[0167] Examples of such barrier layers include, but not limited to, atop-coating layer covering the middle section. When the medical deviceof the present invention is a stent, examples of such barrier layersinclude, but not limited to, a sheath with or without apertures oropenings. Suitable material for making such barrier layer include, butnot limited to, hydrophobic polymers listed in section 2.2, supra.

7. Expandable Stents Having Projecting Elements at Their Ends

[0168] Another embodiment of the present invention is directed to anexpandable stent, such as a balloon-expandable stent having two ends oredges and a tubular sidewall in between the ends. The tubular sidewallcomprises a plurality of struts. The stent also comprises a plurality ofprojecting elements located at or proximate the ends or edges of thestent in its unexpanded state. Each projecting element has two ends. Oneend of the projecting element is attached to or integral with a stentstrut. When the stent is expanded to an expanded state, the end of theprojecting element that is not attached to or integral with a stentstrut defines the end or edge of the expanded stent. Also, the end ofthe unattached projecting element can define the end or edge of thestent in both its expanded and unexpanded state.

[0169]FIG. 21 shows an example of such a stent 210 in its unexpandedstate. The stent 210 comprises two stent ends or edges 211 a and 211 bwith a tubular sidewall 212 therebetween. The tubular sidewall 212comprises or is made up of a plurality of struts 214. In this stent 210the struts 214 are arranged as a plurality of valleys 214 a and apexes214 b. The sidewall comprises a plurality of projecting elements 215,each having two ends 215 a and 215 b. The projecting elements arelocated proximate at least one stent end 211 a and/or 211 b. One end ofthe projecting element, e.g. a first projecting element end 215 a, isattached to or integral with a stent strut 214. Although this figureshows that the first. projecting element end 215 a is attached to orintegral with a stent strut that forms a valley 214 a, the firstprojecting element end 215 a can be attached to or integral with a stentstrut that forms an apex 214 b.

[0170]FIG. 22 shows the stent 210 of FIG. 21 in its expanded state. Whenthe stent 210 is expanded, or in an expanded state the projectingelement ends 215 b that are not attached to or integral with a stentstrut (e.g. the second projecting element ends) are capable of definingat least one end or edge 211 a and/or 211 b of the stent 210. Preferablythe second projecting element ends 215 b can define the stent end(s) 211a and/or 211 b when the stent is in its fully expanded state; howeverthe projecting element ends 215 b can define the stent end(s) 211 aand/or 211 b when the stent is in a partially expanded state that isless than the fully expanded state.

[0171] The projecting elements 215 should have substantially no effecton the expansion of the stent. Moreover, the projecting elements do notradially expand when the stent is radially expanded. More specifically,with reference to FIGS. 21 and 22, when the stent is radially expanded,apex 214 b will radially expand and change in height or length from L toL′, which is less than L. However, because of the configuration of theprojecting element 215, the projecting element will not expand in widthw when the stent is expanded, i.e., the width w of the projectingelement does not change or increase when the stent is radially expanded.Also, the projecting element does not change length when the stent isradially expanded. By not expanding in width when the stent expands, theprojecting element acts as a source of stress relief.

[0172] Furthermore, the projecting elements 215, shown in FIGS. 21 and22 function as sources of stress relief because they are not supportedat their sides as the apexes 214 b are. The projecting elements aresupported at only one print 215 c (FIG. 22) by a stent strut, i.e., theprojecting element is attached or integral with a stent strut only at asingle point of the projecting. In contrast the apexes are supported bystent struts at two points 215 c and 215 d (in FIG. 22). The amount ofsupport from adjacent struts can affect the strain at the end of astent. Also, extension of the projecting elements 215 longitudinallybeyond the apexes of the expanded stent act to relieve the strain. Byextending further longitudinally toward the edge of the stent than theapexes, the projecting elements apply less force to the vessel than theapexes. This creates a region of lower stress between the apexes andnative vessel beyond the end of the projecting elements.

[0173] Also, the projecting elements preferably lie along substantiallythe same plane as the struts of the stent. This way, at least a portionof each projecting element contacts a patient's lumen wall like thestent struts when the stent is placed in a body lumen. In embodiments ofthe expandable stent of the present invention, the projecting elementsare preferably integral with the struts, namely, they are generally madefrom the same material as the struts and are formed as a continuous partof the struts. However, the struts and projecting elements can be madeof different types of materials and are then connected or attached toeach other. Preferably, the projecting elements and struts may bemanufactured simultaneously; for example, struts having projectingelements can be laser-ablated from a plate of metal or polymer. In otherembodiments the projecting elements may be attached to the stent strutsafter the stent is formed.

[0174] The projecting elements may be integral with or attached tostruts at any portion proximate the ends of the unexpanded stent so longas the projecting elements do not hinder the stent from collapsing andexpanding. When the struts are configured as a plurality of apexes andvalleys, the projecting elements may be integral with or attached tostruts at apexes, valleys or anywhere in between. For example, FIG. 21shows a stent in its collapsed or unexpanded state, wherein the stenthas projecting elements 215 integral with a strut forming a valley 214a. FIGS. 23-27a show ends of stents, wherein the projecting elements230, 240, 250, 260, 260 a, 270 and 270 a are integral with or attachedto struts forming apexes 214 b. The projecting elements can bedistributed uniformly or in any other manner proximate the ends of thestent.

[0175] The projecting elements suitable for the present invention may bein any shape including a straight rod, a bent rod, a rod having agreater width at the projecting elements free end (e.g., see FIGS. 22,23, 24 and 27), a rod having a hoop or circle or sphere at the free end(e.g., see FIGS. 26 and 26a), a truncated circle or cone (e.g., see FIG.25). Moreover, the projecting elements can have a serpentine-like orspiral-like shape as shown in FIG. 27a. Also, as shown, e.g., in FIG.27, the length of the projecting elements 270 may vary. Also, as shownin FIG. 27, the free ends of the projecting elements not only define theends of the stent in its expanded state but can also define the stentends when the stent is in its unexpanded state.

[0176] The stent struts 214 may be fabricated from metallic and/orpolymeric materials. Suitable metallic materials include metals andalloys based on titanium (such as nitinol, nickel titanium alloys,thermo-memory alloy materials), stainless steel, tantalum,nickel-chrome, or certain cobalt alloys including cobalt-chromium-nickelalloys such as Elgiloy® and Phynox®. Metallic materials also includeclad composite filaments, such as those disclosed in WO 94/16646.Suitable polymeric materials include without limitation polyurethane andits copolymers, silicone and its copolymers, ethylene vinyl-acetate,polyethylene terephtalate, thermoplastic elastomers, polyvinyl chloride,polyolefins, cellulosics, polyamides, polyesters, polysulfones,polytetrafluorethylenes, polycarbonates, acrylonitrile butadiene styrenecopolymers, acrylics, polylactic acid, polyglycolic acid,polycaprolactone, polylactic acid-polyethylene oxide copolymers,cellulose, collagens, and chitins.

[0177] The projecting elements suitable for the present invention may ormay not comprise the same material as the stent struts. In someembodiments, it is preferable that the projecting elements are made frommaterials that are more flexible than the materials used to form thestruts. When the projecting elements are more flexible than the struts,the strain exerted by the stent end against a body lumen, when the stentis in an expanded state, is reduced thereby reducing the possibility ofrestenosis that may occur at or near the implanted stent ends. Morespecifically, it has been hypothesized that the restenosis which canoccur at or near the ends or edges of a stent implanted in a body lumen,may be caused by a lack of strain relief at or near the ends of thestent. It is believed that the stent struts at the ends of the stentexert too great a pressure against the body tissue that contacts thestent end. Therefore it is desirable to reduce the pressure exertedagainst the body tissue by the stent ends. The inclusion of projectingelements, whose free ends define the ends of the stent when the stent isin an expanded state, reduces the pressure or strain exerted by the endsof the expanded stent. One way that the use of projecting elementsreduces such pressure or strain is by reducing the amount of stentmaterial present at the ends of the expanded stent. Also, the projectingelement may be configured in a shape more flexible than the struts,e.g., thinner and/or narrower than the struts. In this way, theprojecting elements avoid the stress to be concentrated at the edges orends of the stent and reduce the “edge effect.”

[0178] As shown in FIG. 22, by including projecting elements 215, thestent end 211 b, which is defined by the free end or second end of theprojecting elements 215 b, is located at line a-a. If the projectingelements 215 were not included as a part of the stent the end of theexpanded stent would be located at line b-b. As can be seen in FIG. 22,the amount of stent material at line a-a is less than at line b-b. Thus,inclusion of the projecting elements also reduces the amount of stentmaterial at the stent ends, thereby reducing the pressure exerted by thestent ends against the body tissue. In addition to the amount of stentmaterial, as discussed above, the amount of support from adjacent strutsas well as the thickness of the strut impact the strain at the end of astent.

[0179] Furthermore, making the projecting element from materials thatare more flexible than the materials used to make the stent struts alsoreduces the pressure exerted by the ends of an expanded stent againstbody tissue. The use of more flexible material for the projectingelements, whose free end defines the end(s) of the expanded stent,allows the stent to have more “give”, thereby reducing the pressure thestent end exerts against body tissue when the stent is implanted in abody lumen.

[0180] In a preferred embodiment, at least one strut and/or at least oneprojecting element comprises a biologically active material. Suitablebiologically active materials are discussed above in Section 5.2. Thestrut or projecting element can be coated with the biologically activematerial. The coating can further include polymeric materials. Suitablepolymeric materials are set forth above in Section 5.1. Alternatively,the biologically active material can be incorporated into the materialsused to form the struts or projecting elements such as a polymer havinga biologically active material incorporated therein. Moreover, as shownin FIGS. 23 and 24 the projecting elements 230 and 240 can be the shapeof a rod having an end with a greater width at the second projecting endand at least one depression or indentation 231 and 24, respectivelywhich contains the biologically active material 232. The depressions canalso include a polymeric material in addition to the biologically activematerial. The indentations can be in the shape of cavities that canextend partly or entirely through the projecting element.

[0181] In another embodiment, as shown, e.g., in FIGS. 28 and 29 theprojecting elements 280 have openings 281. FIG. 28 shows stent end 211 bwhen the stent is unexpanded. FIG. 29 shows the stent end 211 b when thestent is expanded. A ribbon 282 can be passed or threaded through theopenings 281. The ribbon 282 contains a biologically active material.The ribbon may or may not be elastic as long as it does notsubstantially hinder the stent from expanding. The ribbon may be a tapeand/or a fabric comprising a polymeric material. Suitable polymericmaterials for making the ribbon include without limitation polyurethaneand its copolymers, silicone and its copolymers, ethylene vinyl-acetate,polyethylene terephtalate, thermoplastic elastomers, polyvinyl chloride,polyolefins, cellulosics, polyamides, polyesters, polysulfones,polytetrafluorethylenes, polycarbonates, acrylonitrile butadiene styrenecopolymers, acrylics, polylactic acid, polyglycolic acid,polycaprolactone, polylactic acid-polyethlyene oxide copolymers,cellulose, collagens, and chitins. In some embodiments, the biologicallyactive material is coated on the ribbon. The coating can be applied ontothe ribbon in any method, for example, dipping, spraying, electrostaticdeposition and rolling. In other embodiments, the ribbon is prepared bysoaking a fabric ribbon in a biologically active material solution. Inaddition, the struts and/or projecting elements can include abiologically active material, such as a coating comprising abiologically active material.

[0182] The description contained herein is for purposes of illustrationand not for purposes of limitation. Changes and modifications may bemade to the embodiments of the description and still be within the scopeof the invention. Furthermore, obvious changes, modifications orvariations will occur to those skilled in the art. Also, all referencescited above are incorporated herein, in their entirety, for all purposesrelated to this disclosure.

We claim:
 1. An expandable stent comprising two ends and a tubularsidewall between the two ends, wherein the sidewall comprises aplurality of struts, and a plurality of projecting elements locatedproximate at least one stent end; wherein each projecting elementcomprises a first end and a second end; wherein the first projectingelement end is integral with or attached to a strut; wherein the secondprojecting element end is capable of defining at least one stent endwhen the stent is in an expanded position; and wherein at least one ofthe struts or at least one of the projecting elements comprises abiologically active material.
 2. The stent of claim 1 wherein theprojecting element is configured such that the projecting element doesnot expand in width when the stent is radially expanded.
 3. The stent ofclaim 1 wherein the projecting element is integral with or attached to asingle strut only at a single point on the projecting element.
 4. Thestent of claim 1 wherein at least one strut and at least one projectingelement comprise the biologically active material.
 5. The stent of claim1 wherein all of the struts and all of the projecting elements comprisethe biologically active material.
 6. The stent of claim 1 wherein thefirst projecting element end is integral with the strut.
 7. The stent ofclaim 1 wherein the strut or projecting element that comprises thebiologically active material comprises a coating containing thebiologically active material.
 8. The stent of claim 7 wherein thecoating further comprises a polymeric material.
 9. The stent of claim 1wherein the biologically active material is a macrolide selected fromsirolimus or everolimus.
 10. The stent of claim 1 wherein thebiologically active material is selected from paclitaxel, a derivativeof paclitaxel or an analog of paclitaxel.
 11. The stent of claim 1,wherein at least one projecting element is configured in a shapeselected from a straight rod, a bent rod, a rod having an end with agreater width at the second projecting element end, a rod having a hoopat the second projecting element end, or a truncated circle.
 12. Thestent of claim 1, wherein at least one projecting element is configuredin a shape of a rod having an end with a greater width at the secondprojecting element end, and at least one indentation for containing thebiologically active material located at the second projecting elementend.
 13. The stent of claim 1, wherein at least some of the projectingelements comprise an opening therein and wherein the stent furthercomprises a ribbon comprising the biologically active material, andwherein the ribbon passes through at least one of the openings in theprojecting elements.
 14. The stent of claim 1, wherein the projectingelements are distributed uniformly at the ends of the stent.
 15. Thestent of claim 1, wherein the struts are configured as a plurality ofapexes and valleys, and wherein the projecting elements are integralwith or attached to at least one of the apexes.
 16. The stent of claim1, wherein the struts are configured as a plurality of apexes andvalleys, and wherein the projecting elements are integral with orattached to at least one of the valleys.
 17. The stent of claim 1,wherein the struts and the projecting elements comprise the samematerial.
 18. The stent of claim 1, wherein the struts comprise a firstmaterial and the projecting elements comprise a second material.
 19. Thestent of claim 18, wherein the second material is more flexible than thefirst material.
 20. A balloon expandable stent comprising two ends and atubular sidewall between the two ends, wherein the sidewall comprises aplurality of struts; and a plurality of projecting elements proximate atleast one stent end; and wherein each projecting element comprises afirst end and a second end; and wherein the first projecting element endis integral with or attached to a strut; and wherein the secondprojecting element end is capable of defining at least one stent endwhen the stent is in an expanded position; and wherein at least one ofthe projecting elements comprise a biologically active material.
 21. Thestent of claim 20 wherein the projecting element is configured such thatthe projecting element does not expand in width when the stent isradially expanded.
 22. The stent of claim 20 wherein the projectingelement is integral with or attached to a single strut only at a singlepoint on the projecting element.
 23. The stent of claim 20 wherein atleast one strut comprises the biologically active material.
 24. Thestent of claim 20 wherein at least one projecting element comprises acoating comprising the biologically active material.
 25. The stent ofclaim 20 wherein all of the struts and the projecting elements comprisea coating comprising the biologically active material.
 26. The stent ofclaim 20 wherein the biologically active material is selected frompaclitaxel, a derivative of paclitaxel or an analog of paclitaxel.
 27. Asystem comprising a balloon expandable stent and a balloon catheterhaving an inflatable balloon for expanding the stent to an expandedposition, wherein the stent comprises two ends and a tubular sidewallbetween the two ends, wherein the sidewall comprises a plurality ofstruts; and a plurality of projecting elements proximate at least onestent end; wherein each projecting element comprises a first end and asecond end; and wherein the first projecting element end is integralwith or attached to a strut; and wherein the second projecting elementend is capable of defining at least one stent end when the stent is inthe expanded position; wherein at least one of the struts or one of theprojecting elements comprise a biologically active material.
 28. Thestent of claim 27 wherein the projecting element is configured such thatthe projecting element does not expand in width when the stent isradially expanded.
 29. The stent of claim 27 wherein the projectingelement is integral with or attached to a single strut only at a singlepoint on the projecting element.
 30. The system of claim 27 wherein atleast one strut and at least one projecting element comprises thebiologically active material.
 31. The system of claim 27 wherein thebiologically active material is selected from paclitaxel, a derivativeof paclitaxel or an analog of paclitaxel.
 32. The stent of claim 27wherein the projecting elements are integral with the struts.